Ionic polypeptides with unusual helical stability

Water-soluble peptides that adopt stable helical conformations are attractive motifs because of their importance in basic science and their broad utility in medicine and biotechnology. Incorporating charged amino-acid residues to improve peptide solubility, however, usually leads to reduced helical stability because of increased side-chain charge repulsion, reduced side-chain hydrophobicity and the disruption of intramolecular hydrogen bonding. Here, we show that water-soluble, ultra-stable a-helical polypeptides can be produced by elongating charge-containing amino-acid side chains to position the charges distally from the polypeptide backbone. The strategy has been successfully applied to the design and synthesis of water-soluble polypeptides bearing long, charged side chains and various functional moieties that possess unusual helical stability against changing environmental conditions, including changes in the pH and temperature and the presence of denaturing reagents.